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"Hematotoksisitas pada leukemia limfoblastik akut (LLA) anak selama terapi fase pemeliharaan, merupakan hal penting, karena dapat menyebabkan kondisi mengancam jiwa dan penghentian dini terapi, yang dapat meningkatkan risiko relaps. Untuk menghindari hematotoksisitas, American Society for Clinical Pharmacology and Therapeutics merekomendasikan penyesuaian dosis awal merkaptopurin (6MP) berdasarkan genotip enzim pemetabolisme 6MP yaitu thiopurine S-methyl transferase (TPMT), berdasarkan studi-studi sebelumnya polimorfisme enzim tersebut memengaruhi kadar metabolit aktif 6MP dan hematotoksisitas. Penelitian ini bertujuan untuk mengetahui prevalensi hematotoksisitas dan melihat hubungannya dengan genotip TPMT, fenotip TPMT, dan karakteristik pada pasien LLA anak di Indonesia. Studi potong lintang dilakukan di RS Cipto Mangunkusumo dan RS Kanker Dharmais pada bulan Juni 2017–Oktober 2018 terhadap 106 pasien LLA anak yang sedang mendapatkan 6MP minimal 1 bulan pada terapi fase pemeliharaan. Prevalensi hematotoksisitas pada fase pemeliharaan pasien LLA anak di Indonesia 71,7%, dengan neutropenia 51,9%, anemia 44,3%, dan trombositopenia 6,6%. Neutropenia tingkat 3–4 sebesar 9,4%. Alel mutan yang ditemukan hanya TPMT*3C dengan frekuensi 0,95%. Kadar 6TGN, 6MeMP dan rasio kadar 6MeMP/6TGN sangat bervariasi, yaitu 6–234,04 pmol/8x10⁸ eritrosit, 3,5–3167,01 pmol/8x10⁸ eritrosit, dan 0,06–100,64 pmol/8x10⁸ eritrosit, secara berurutan. Sebesar 76,4% pasien berusia antara 1–10 tahun dan > 95% pasien memiliki status gizi dan kadar albumin normal. Proporsi pasien berdasarkan stratifikasi risiko dan dosis harian 6MP sebanding. Tidak terdapat hubungan antara hematotoksisitas dengan genotip TPMT, usia, status gizi, kadar albumin, stratifikasi risiko, cara pemberian dosis harian 6MP, dan pemberian bersama kotrimoksazol. Faktor yang berhubungan dengan hematotoksisitas adalah fenotip TPMT: kadar 6MeMP (p = 0,004) dan rasio kadar 6MeMP/6TGN (p = 0,010). IMT ≤ 16,6 kg/m2 berhubungan dengan anemia dan kadar albumin serum ≤ 4,2 g/dL berhubungan dengan trombositopenia. Tidak terdapat hubungan antara genotip dengan fenotip TPMT pada pasien LLA anak di Indonesia. Kesimpulan: Hematotoksisitas tidak berhubungan dengan genotip TPMT dan karakteristik pasien. Fenotip TPMT berhubungan dengan hematotoksisitas, namun kurang kuat untuk memprediksi hematotoksisitas.

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Hematotoxicity in acute lymphoblastic leukemia (ALL) children during maintenance phase therapy is important, because it can cause life-threatening conditions and it is the major cause of drug discontinuation, which can increase the risk of relapse. To reduce hematotoxicity, American Society for Clinical Pharmacology and Therapeutics recommended to adjust starting dose of mercaptopurine (6MP) based on patient's genotype of thiopurine S-methyl transferase (TPMT), that affected 6MP active metabolite levels and hematotoxicity.

The aim of the study was to determine the prevalence of hematotoxicity and factors that affecting hematotoxicity, focus on genotype and phenotype of TPMT. A cross-sectional study was conducted at Cipto Mangunkusumo Hospital and Dharmais Cancer Hospital in June 2017–October 2018 for 106 LLA patients who were receiving at least 1 month of 6MP during maintenance therapy.

The prevalence of neutropenia, anemia, and thrombocytopenia were 51.9%, 44.3%, and 6.6%, respectively. We found only TPMT *3C with a frequency of 0.95%. Erythrocyte levels of 6TGN, 6MeMP, and ratio of 6MeMP/6TGN levels vary greatly, 6–234,04 pmol/8x10⁸ RBC, 3,5–3167,01 pmol/8x10⁸ RBC, and 0,06–100,64 pmol/8x10⁸ RBC. About 76.4% of patients aged 1–10 years, and > 95% of patients had normal nutritional status and serum albumin levels. The proportion of patients based on risk stratification and daily dose of 6MP were comparable. There was no association between hematotoxicity and genotype TPMT, age, nutritional status, serum albumin levels, risk stratification, daily dose of 6MP, and co-administration of cotrimoxazole. The factor associated with hematotoxicity was the TPMT phenotype: 6MeMP levels (p = 0.004) and the ratio of 6MeMP/6TGN levels (p = 0.010). BMI ≤ 16.6 kg/m2 was associated with anemia and serum albumin level ≤ 4.2 g/dL was associated with thrombocytopenia. There was no relationship between genotype and the TPMT phenotype in pediatric LLA patients in Indonesia.

Conclusion: Hematotoxicity is not associated with TPMT genotype and patient characteristics. The TPMT phenotype is associated with hematotoxicity but is not strong enough at predicting hematotoxicity."

"ABSTRAKLatar belakang: Pada semua sindrom epilepsi, epilepsi lobus temporal ELT memiliki kemungkinan paling besar untuk menjadi resisten terhadap obat.Polimorfisme gen multidrug resistant-1 MDR1 C3435T dicurigai sebagai salahsatu penyebabnya. Di RS Cipto Mangunkusumo RSCM , sebagai pusat rujukannasional, prevalensi ELT potensial resisten obat adalah 84.51 dan duapertiganya dalam terapi karbamazepin KBZ .Tujuan: Mengetahui polimorfisme dan ekspresi gen MDR1 C3435T serta kadarplasma KBZ pada penderita epilepsi yang responsif dan resisten terhadap obat.Metode: Penelitian potong lintang komparatif dilakukan di RSCM dari Juni 2015sampai Desember 2016. Penderita ELT dipilih secara konsekutif. Kelompokkontrol terdiri dari subjek sehat tanpa riwayat epilepsi. Identifikasi genotipemenggunakan teknik restriction Fragment Length Polymorphism PCR denganenzim restriksi Mbo1. Pemeriksaan kadar plasma KBZ menggunakan HighPerformance Liquid Chromatography. Ekspresi mRNA dengan metodesequencing and real time quantitative PCR.Hasil: Didapatkan 61 subjek dan 25 kontrol. Sebaran genotipe TT 71,43 danalel T genotipe CT dan TT lebih tinggi pada grup resisten x= 10,41; p =0,001 . Terdapat korelasi sangat kuat antara dosis dan kadar plasma KBZ padagrup responsif r = 0,75; p = 0,000 dengan rerata dosis 405,21 226,50mg dankadar plasma 7,59 2,32mcg/mL. Ekspresi kuantitatif relatif Rq mRNA palingtinggi pada grup kontrol diikuti resisten dan responsif. Genotipe TT menunjukkanRq yang berbeda pada tiap grup. Terdapat perbedaan bermakna antara dosis dankadar plasma KBZ pada masing-masing genotipe tiap grup, terutama antaragenotipe CT reponsif dengan semua genotipe grup resisten.Kesimpulan: Genotipe TT dan alel T MDR1 C3435T secara statistik berhubungandengan dosis dan kadar plasma KBZ yang lebih tinggi pada ELT resisten obat.

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ABSTRACTBackground Among epilepsy syndrome, temporal lobe epilepsy TLE has thehighest probability to become drug resistant. Multidrug resistant 1 MDR1 C3435T polymorphism was suspected to be one of the caused. In CiptoMangunkusumo hospital RSCM , as the national reference hospital, potentialdrug resistant epilepsy prevalence was 84.51 and carbamazepine CBZ usagein two third of the patients.Objective This study was performed to learn about MDR1 C3435T polymorphismand expressions, and CBZ plasma concentration in drug responsive and resistanttemporal lobe epilepsy patients.Methods A comparative cross sectional study was performed in RSCM. TLEpatients were selected consecutively. Healthy people were also selected as thecontrol group. Restriction Fragment Length Polymorphism PCR technique withMbo1 restriction enzyme was used to identify the genes. High Performance LiquidChromatography method was used to determine CBZ concentration in plasma.mRNA expressions identification were using sequencing and real timequantitative PCR methods.Result There were 61 subjects in study group and 25 in control group. Frequencyof TT genotype 71.43 and T allele CT and TT genotype were higher inresistant one x2 10.41, p 0.001 . There was a very strong correlationsbetween CBZ plasma concentration in drug responsive epilepsy r 0.75, p 0.000 in mean dosage of 405,21 226,50mg and plasma concentration of 7,59 2,32mcg mL. mRNA expressions were highest in control group followed byresistant and responsive ones. TT genotype expression was relatively different ineach group. There were signifant differences between genotype in each groupwith CBZ dosage and plasma concentration, especially in CT responsivecompare to all genotypes in resistant group.Conclusion TT genotype and T allele of MDR1 C3435T statistically associatedwith higher CBZ dosage and plasma concentration in drug resistant TLE patients."

"Relaps masih menjadi masalah dalam eradikasi malaria vivaks. Primakuin adalah satu-satunya antihipnozoit yang saat ini tersedia di pasaran. Efikasi primakuin diperoleh oleh farmakokinetik dan farmakodinamik obat. Kemampuan CYP2D6 memetabolisme primakuin menjadi bentuk aktif akan memengaruhi kadar primakuin dan efikasi klinisnya. Pada penelitian ini dilakukan analisis farmakokinetik dan farmakodinamik primakuin dengan pendekatan populasi pada subjek dengan malaria vivaks; serta menganalisis hubungan variasi jumlah salinan gen CYP2D6 dengan kejadian relaps.Subjek studi adalah 174 orang Tentara Nasional Indonesia yang terinfeksi malaria vivaks dan diterapi dengan kombinasi skizontisida dan primakuin selama 14 hari. Kejadian relaps diamati selama satu tahun. Model farmakokinetik-farmakodinamik primakuin yang dikembangkan dengan metode mixed effect non linier menggunakan piranti lunak NONMEM versi 7.4.1. Kuantifikasi jumlah salinan gen CYP2D6 dilakukan pada 49 subjek. Jumlah salinan ditentukan berdasarkan nilai Cq hasil amplifikasi intron 6 dengan qPCR real-time. Jumlah salinan dihitung sesuai dengan rumus 2-ΔΔCq x jumlah salinan DNA Kalibrator, ΔΔCq = ΔCq (kalibrator)  ΔCq (sampel) dan ΔCq = Cq (CYP2D6) - Cq (RNAse P). Hubungan jumlah salinan gen CYP2D6 dan kejadian relaps malaria vivaks dianalisis dengan uji Chi-square.Hasil penelitian menunjukkan bahwa kadar primakuin plasma paling baik dideskripsikan oleh model satu kompartemen dengan penyerapan orde pertama. Berat badan diimplementasikan sebagai fungsi alometrik pada clearance (CL) dan distribusi volume (Vd). Piperakuin maupun pironaridin menurunkan CL dan Vd primakuin sebesar 3354%. Faktor genetik CYPD6 tidak memengaruhi CL primakuin. Risiko kejadian relaps malaria vivaks dideskripsikan dengan model constant hazard pada model time-to-event. Peningkatan satu poin skor aktivitas gen CYP2D6 menurunkan risiko relaps sebesar 88,3%, sehingga dapat disangkal bahwa faktor genetik CYP2D6 menjadi salah satu faktor yang dapat memengaruhi risiko kambuh vivaks malaria. Tidak didapatkan hubungan antara AUC primakuin dan kejadian relaps, sehingga hasil ini tidak dapat digunakan untuk menghitung dosis primakuin yang optimal. Kuantifikasi jumlah salinan gen CYPD6 dilakukan pada 21 subjek relaps dan 28 subjek kontrol. Mayoritas subjek memiliki jumlah salinan ≥ 2 (39 dari 49 orang). Tidak ditemukan hubungan antara jumlah salinan gen CYP2D6 dan kejadian relaps (p = 0,155).Relapse is still a problem in vivax malaria eradication. Primakuine is the only antihipnozoite currently available on the market. The efficacy of primaquine is obtained by the pharmacokinetics and pharmacodynamics of the drug. The ability of CYP2D6 to metabolize primaquine to its active form will affect primakuine levels and clinical efficacy. In this study, a pharmacokinetic and pharmacodynamic analysis of primaquine was carried out with a population approach in subjects with vivax malaria; and to analyze the relationship between variations in the number of copies of the CYP2D6 gene with the incidence of relapse.Study subjects were 174 Indonesian National Armed Forces infected with vivax malaria and treated with a combination of schizonticides and primaquine for 14 days. Relapse incidence was observed for one year. The primakuine pharmacokinetic-pharmacodynamic model was developed using a non-linear mixed effect method using NONMEM software version 7.4.1. Quantification of the number of copies of the CYP2D6 gene was performed in 49 subjects. The number of copies is determined based on the Cq value of the intron 6 amplification with real-time qPCR. The number of copies is calculated according to the formula 2-ΔΔCq x number of copies of the DNA Calibrator, ΔΔCq = ΔCq (calibrator)  ΔCq (sample) and ΔCq = Cq (CYP2D6) - Cq (RNAse P). The association between copy number of CYP2D6 gene and the incidence of vivax malaria relapse was analyzed using Chi-square test.The results showed that plasma primquine levels were best described by a one-compartment model with first-order absorption. Body weight is implemented as an allometric function on clearance (CL) and volume distribution (Vd). Piperakuine and pyronaridin reduce CL and Vd primakuin by 3354%. CYPD6 genetic factor does not affect CL primaquine. The risk of vivax malaria relapse was described using the constant hazard model in the time-to-event model. One point increase in the CYP2D6 gene activity score reduced the risk of relapse by 88.3%, so it can be denied that CYP2D6 genetic factor is one of the factors that can affect the risk of malaria vivax relapse. There was no relationship between AUC of primaquine and the incidence of relapse, so these results cannot be used to calculate the optimal primquine dose. CYPD6 gene copy count quantification was performed in 21 relapsed subjects and 28 control subjects. The majority of subjects had a number of copies ≥ 2 (39 of 49 people). No association was found between the number of copies of the CYP2D6 gene and the incidence of relapse (p = 0.155)."

"Latar belakang: Terapi farmakologi kanker payudara triple negative (KPTN)terbatas pada obat sitostatika seperti doksorubisin. Namun, resistensi doksorubisinsulit dihindari. Salah satu jalur pensinyalan yang penting pada resistensiKPTN terhadap doksorubisn adalah TGF-β. TMEPAI (transmembran prostatandrogen-induced protein), regulator negatif sekaligus gen target pada jalur TGF-β diduga merupakan salah satu kunci dalam resistensi KPTN terhadapdoksorubisin.Metode: Teknik CRISPR-Cas9 digunakan untuk menghilangkan TMEPAI padagalur sel KPTN, BT549. Sel diberi perlakuan TGF-β 2 ng / mL dan doksorubisinselama 24 jam. Pengukuran konsentrasi sitotoksik doksorubisin pada 50%populasi sel (CC50) dilakukan terhadap sel KPTN wildtype (WT) dan knock out(KO). Setelah itu, sel dipanen dan dihitung. Rantai Polimerase Waktu NyataReaction (RT-PCR) dan western blot (WB) digunakan untuk mengukur tingkatekspresi penande proliferasi, apoptosis, EMT, dan transporter. Selain itu, SMADyang terfosforilasi dan aktivitas PI3K / Akt juga belajar.Hasil: Galur sel yang tidak memiliki TMEPAI (KO) berhasil diperoleh dari selKPTN, BT549. Sel WT terbukti lebih resistan terhadap doksorubisindibandingkan sel KO yang ditunjukkan dengan peningkatan CC50 dan Ki-67.TMEPAI menurunkan efek apoptosis doksorubisin dengan memodulasi ekspresibcl-2 dan kaspase-3, namun tidak kaspase-9 dan bax. Efek TMEPAI mengurangidoksorubisin dengan menekan fosforilasi SMAD. Namun TMEPAI meningkatkanpenghambatan PI3K / Akt oleh doksorubisin. TMEPAI juga meningkatkan EMTdan transporter efluks yang diinduksi oleh doksorubisin.Kesimpulan: TMEPAI terhadap pertarungan dalam resistensi sel KPTNdoksorubisin melalui aktivasi jalur sinyal TGF-β non-canonical beserta proteindan gen targetnya.Background: Triple negative breast cancer (KPTN) pharmacological therapylimited to cytostatic drugs such as doxorubicin. However, doxorubicin resistancehard to avoid. One of the important signaling pathways of resistanceKPTN against doxorubisn is TGF-β. TMEPAI (transmembrane prostateandrogen-induced protein), a negative regulator as well as a target gene in the TGF-β is thought to be one of the keys in the resistance of KPTN todoxorubicin.Method: The CRISPR-Cas9 technique was used to remove TMEPAI onKPTN cell lines, BT549. Cells were treated with TGF-β 2 ng / mL and doxorubicinfor 24 hours. Measurement of the cytotoxic concentration of doxorubicin at 50%cell population (CC50) was carried out against wildtype KPTN (WT) cells and knockout(KO). After that, cells are harvested and counted. Real Time Polymerase ChainReaction (RT-PCR) and western blot (WB) were used to measure levelsexpression markers of proliferation, apoptosis, EMT, and transporters. Apart from that, SMADthe phosphorylated and PI3K / Akt activities also learn.Results: Cell lines that did not have TMEPAI (KO) were obtained from the cellsKPTN, BT549. WT cells have been shown to be more resistant to doxorubicincompared to cell knockout shown with increased CC50 and Ki-67.TMEPAI decreases the apoptotic effect of doxorubicin by modulating expressionbcl-2 and caspase-3, but not caspase-9 and bax. TMEPAI reducing effectsdoxorubicin by suppressing SMAD phosphorylation. However TMEPAI is improvingPI3K / Akt inhibition by doxorubicin. TMEPAI also increases EMTand doxorubicin-induced efflux transporters.Conclusion: TMEPAI against the fight against KPTN cell resistancedoxorubicin via activation of the non-canonical TGF-β signaling pathway along with proteinsand its target genes."